Selected slow postsynaptic transmitter actions produce long- lasting changes of the electrical properties of nerve and muscle cells through various molecular and ionic mechanisms. Here the study of the biochemical cascade underlying the slow transmitter response that mediates the presynaptic inhibition of transmitter release in the central nervous system of the snail Aplysia is proposed. FMRFamide, an endogenous tetra-peptide, has been recently shown to induce a slow IPSP in the mechanosensory neurons (SN) of Aplysia and to depress transmitter release from the same cells. These actions are due to a decrease of the macroscopic voltage- dependent Ca++ current and to an increased opening of a specific K+ channel, the S channel (the same K+ channel is closed by serotonin and cAMP in the SNs, a mechanism underlying the facilitation of transmitter release). In addition, FMRFa reopens S channels closed by serotonin. Preliminary experiments suggest that FMRFa action is mimicked by dopamine (DA), is cAMP- independent, but is closely linked to the stimulation of arachidonic acid (AA) metabolism. The patch-clamp technique will be applied to Aplysia SNs in culture to investigate this novel action of AA metabolism, the coupling of a transmitter receptor to the modulation of ion channels in control of synaptic efficacy. The work should answer various specific questions, including: 1) Is the AA cascade directly mediating the membrane conductance changes elicited in SNs by these inhibitory transmitters? 2) Since transmitter action has multiple effects on the SN membrane conductances and the AA cascade has several branch points, are individual metabolites mediating specific components of the inhibitory response? 3) What is the link between surface receptor stimulation and phospholipase activation, and between the active AA metabolite and the ion channel modulation? In addition, 4) DA mechanism of action and its interplay with FMRFa will be investigated, and 5) the characterization of the Ca current modulation will be performed. An understanding of the nature of these transmitter responses in the Aplysia nervous system will provide insight into two general areas: the mechanism of presynaptic inhibition, a form of synaptic plasticity phylogenetically widespread, and the role in nerve cells of the AA metabolism, a ubiquitous signalling system in animal cells.